3,11-diketo-17,20-dihydroxypregnanes and process



Patented Jan. 10, 1 950 UNITED STATES PATENT OFFICE *PKEGNANES AND PROCESS vlaewisfflastings Sarett, Princeton, N. J ,assignor ltoiMemk & 410., -I.nc., Rahway, -a corpora tiomof New-Jersey "No Drawin-g. Application July 13,1946, :Serial No. 683,427

17 Claims. (Cl. 260397.4)

whereinR-has the'significance "above defined. In the following description of the invention, the

tstereochem'ical relationship 'of rings li and B is fintiicatetliinitheiormulae'bya sdlid line'represent- 'frngitlremvalenceihondiinttre eismoriflguration.

droxyjpregnane can'he prepared by-reactions represented generically as follows:

wherein R is acyl.

The reactions indicatediabove are conducted as follows: The starting material, A 3,11-diketopregnene (1) which can beprepared as disclosed in my co-pending applications, Serial No. 605,194, filed, July 14, 1945, now abandoned; and Serial No. 687,982 filed August2, I946, is reacted with an agent capable of converting an olefinic bond to the corresponding glycol, such as osmium tetroxide, or hydrogen peroxide in contact with a catalytic amount of osmium tetroxide, whereby the ethylenic linkage is'converted to the corresponding glycol to produce .3;-11-diketo-17,20-dihydroxy-pregnane' (2);; this compound is reacted with an acylating agent F-t'o :produce 3,11-diketo- 17-hydroxy-20-acyloxy pregnane (3) which can be readily purified, as :for example by recrystallization from a solvent. lIhe :pure 20-acy1oxy pregnane can then be hydrolyzedto produce substantially pure 3,11-diketoeili'l;20-dihydroxy-pregnane.

When the starting material, said A "-=-3,11-diketo-pregnane (1), is prepared according to the preferred processes described in my copending applications hereinabove referred to, it is obtained admixed with the corresponding A isomer, compound (4) below, from which it is not 7 readily separated. Accordingly, I prefer to react said mixture of A -3,1l-diketo-pregnene (1) and A -3,1I-diketo-pregnene (4) which can be represented by the following structural formulae:

directly with osmium :tetroxide; this is accomplished Joy dissolvingsajid mixture in asubstantially inert solvent, as for example, a dialkyl ether such as ethylether, and adding a solution of osmium tetroxide thereto. A tertiary amine, such as pyridine, quinoline, picoline, and the like, may then be added to this solution and the mixture allowed to react, preferably at a temperature between about O. C. and 20 C. The reaction mixture is allowed to stand for several hours at about C. to complete crystallization of the osmate esters which are removed by filtration and then hydrolyzed by treating with an aqueous solution of an alkaline reducing agent, as for example, sodium sulfite. The hydrolysis mixture is filtered and the filtrate evaporated to small volume and the mixture of stereoisomeric glycols extracted therefrom by means of a chlorinated hydrocarbon :solvent, such as chloroform, ethylene dichloride,

and the like; the solvent is then evaporated to produce a crude mixture containing 3,11-diketo- 1'7,20,-dihydroxy-pregnane (2),, 3,11-diketo-20- (a), 21-dihydroxy-pregnane (5) and 3,1 1 -diketo- 20 3), 21-dihydroxy-pregnane (6), represented by the following structural formulae;

r (6) The mixture of diketo-dihydroxy-pregnanes is then reacted with a cyclic anhydride of a dicarboxylic acid, as for example, succinic anhydride,

' p tiary amine such as pyridine, quinoline, picoline and the like, whereby the primary hydroxyl groups present in the ,stereoisomers of 3,11-diketo-20,21-dihydroxy-pregnane are preferentially esterified 'to-produce the corresponding stereoisomers of 3,1I-diketO-ZO-Hydr Xy-ZI-(omegacarboxy-acyloxy)-pregnane (7), which can be represented by the-following structural formula: onk'oeoo-ia-coon CH H (7) wherein B is an alkylene, arylene or aralkylene radical. p

The reactionmixture is'mixed with water to destroy unreacted anhydride and the resulting mixture is evaporated substantially to dryness, preferably under reduced pressure. The residual material, which consists of the isomeric 3,11- diketo-20-hydroxy-20- (omega-carboxy-acyloxy) pregnane (7) admixed with unesterified 3,11- diketo-17,20-dihydroxy-pregnane is treated with an aqueous alkaline s01u tion,such as. aqueous sodium carbonate solution, and a water-immiscible solvent. Although it is preferred to employ chlorinated hydrocarbon solvent, asfor example, chloroform, ethylene dichloride, and the like, it is to be understood that the invention is not confined thereto, since most other organic water-immiscible solvents are operable, as for example dialkyl ethers, esters, hydrocarbon solvents, and the like. The non-aqueous 'layer, which contains the desired 3,11-diketo-17,20-dihydroxy-pregnane (2) is separated from the aqueous solution which contains the salts of the half esters (7) of the stereoisomeric 3,11-diketo- -20,21-dihydroxy-pregnanes. Evaporation of this non-aqueous layer yields crude 3,11-diketo-17,20- dihydroxy-pregnane (2), substantially uncontaminated by 20,21-dihydroxy-1pregnane derivative. V The crude V 3,11-diketoe1 7,20-dihydroxy pregnane is then reacted with an acylating agent such as acetic anhydride, acetyl chloride, benzoyl chloride,propionic anliydride, butyric anhydride,

and the like, prei'erably-mmhe presence:ofja; tiary nitrogen base to :producethsurmsmnding :3','1l.-diketo .--1'7'--hydroxyg20acy1oxy --pregnane; The reaction can be carried out at room tempereLture; .butthetreaction mixture can'zbe heated, "it desired, to about 1009 C.:..or higher: Whemthe acylating agent. employed comprises: acetic :an-

hydride and pyridine; and these are .reacted with.

der' saponifying conditions to produce: substantially pure 3,11-diketo-17 ,20-..dihydroxy-pregnane; Hydrolyzing agents operable for this purpose'in clude' alkali hydroxides, carbonates: andi bicarous-organic solvent solution. It is presentlyapre ferred to use :an aqueous alcoholic solution containing a mixture of alkali carbonate and alkali .1

bicarbonate, .as, for example, an aqueous methanol solution, containing both potassium carbonate and potassium bicarbonate. The reactionis best carried out at about C.,'but higher temperatures' canbe employedyif desired; The pure 3,11-diketo-17,20-dihydroxy pregnane can be isolated from the hydrolyzed'solution by .any-.con-

venient:method, as for example, by evaporating to dryness; itcan then .be separated frominorganic solvents by extracting the residue with'sa.

halogenated hydrocarbon'solvent; such as chloroform, ethylene dichloride, and the like,..from which the .product is obtainedi'in crystalline aform upon evaporation ofthe solvent. Further purification can be effected, if desired, by recrystallizing this product from an ester of an aliphatic acid such as ethyl acetate.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Examplev 1 About 9.65 g. of a mixture containing A and M -3,ll-diketmpregnene is dissolved in about cc. of absolute ether, and a solution containing about 8.0 g. of osmium tetroxide in about 50 cc. of absolute ether is added thereto. About 2.4 cc. of pyridine is then added and the mixture is allowed to stand at about 20 C. for approximately 1 hour and then at about 0 C. for approximately 36 hours. The precipitated osmate esters are removed by filtration, suspended in about 350 cc. of alcohol and a solution of about g. of sodium sulfite in about 240 cc. of hot water is added thereto and the mixture refluxed for approximately 3% hrs. The mixture is then; filtered and the insoluble material extracted twice with approximately 200 cc. portions of hot alcohol and the alcohol extracts combined with the This filtrate is then evaporated under reduced pressure to a small volume, diluted. with water and extracted with chloroform. The chloroform layer is washed with water and evapinitial filtrate.

orated to dryness under reduced pressure to pro- 6 duceacrude-mixturezwhich contains ail -dilato- 17 201--:dihydroxy-pregnane, .-3;11 .-diketo420.i (a?) 321idihydroxyepreg'nane and. 3,'11-'diketo-'20.(p).', .21"-

"dihydroxyapregnane.

The separation of .:3;1 1-diketo- IZZO-dihydroxypregnane from; the stereoisomeric: 3, -diketo- $20.2 l-dihydroxy-pregnanes is achieved. bydissolvingt-in about 9.05 g. :of; the "mixture innabout=25 I C(L-"Of pyridine, heating-the. solution :to about 95 C. and adding thereto about 5.0 g. of succinicqanshydride: The mixture .is heated Y at about'z95? C. for: 'approxmately 15: minutes. additional. time, .about:5-.cc.- of-water is addedto the ;hot solution to edecompose' excess .succinic anhydride and the pyridine then evaporated therefrom .under re,- ducednpressure. The. residual material issdissolvedin chloroform, the chloroform solution .is-vwashedwith dilute hydrochloric acid. tore;- :move' traces-poi pyridine, ,then with water; and =the.=hemi-sucoinates of. the; stereoisomeric:3;11e- .diketo.-20,2l-dihydroxy-pregnanes are final'lyrexe .tractedapthercfrcm as. their potassium salts,

.bonates, alkalineeearth hydroxides, mineral- -acids and the likewhich can-beiusedin water or'aqueemeans: of; a1 10% aqueous. potassium carbonate 'PSOIutiOD.

The-chloroform extract which contains the non-acidic. -3;l1.diketo.- 17,20 --dihydroxyepneg5- nanewisc'eyaporatedtmdryness to produceabout 3.6 5;.- of crude material; This-impurezproductiis dissolved :in asolution"containingiabout cc. of -.pyridinc-and :about 1 5 .cc. of acetic? anhydridegand the-resulting solution heated .on a steam bath .ior approximately hour. ,The,.-s01ution.is cooled,

. water. isadded and the .-.crystallinev product: re.-

.covered abyj filtration and purified vby crystallization-from benzene alcohol and :finally from. ben- .zene to produce.substantiallypure 3,; diketoi- 1Lhydroxy-20-acetoxy=pregnane; 22'1- 2295 C..('corr.) (w)p= -l-;? ;(acetone').

L'About l-.80:- g. oi- 3,11-diketo+l7ehydroxy mli- .acetoxy pregnane issadded :to :a. mixture. contains ihgabeutdBO-cc. of :methanol, about 30cc. water. about 1.8 g. of potassium bicarbonate and about 0.9 g. of potassium carbonate. The mixture is heated under reflux until the crystals have dissolved and the mixture is then allowed to stand at about 25 C. for approximately 40 hours. The methanol is then evaporated under reduced pressure, the residue extracted with chloroform and the chloroform solution washed with water. The chloroform solution is then evaporated to dryness and the residue recrystallized repeatedly from ethyl acetate to produce pure 3,11-diketo- 1'7,20-dih.ydrorxy-pregnane;; M. P. 186-18'7 (corn); (oc)D=|-47 (acetone).

Various changes and modifications may be made in my process as described without departing from the scope of my invention. To the extent that these changes and modifications are within the purview of the annexed claims, they are to be considered as part of my invention.

I claim:

1. The process of preparing 3,11-diketo-l7,20- dihydroxy pregnane in substantially pure form, which comprises reacting a mixture containing A 3,11-diketo-pregnane and A -3,11-diketopregnane with a compound selected from the class which consists of osmium tetroxide and hydrogen peroxide to produce a mixture containing 3,11-diketo-l7,20-dihydroxy pregnane, 3,11- diketo 20 alpha 21 dihydroxy pregnane, and 3,1 1 -diketo-20beta-2l -hydroxy-pregnane; reacting this mixture with a cyclic anhydride of a dicarboxylic acid to convert the 20,21-dihydroxy -stereo'isomers to the corresponding stereoisomers of 3,11-diketo-20-hydroxy-21-(carboxy-acyloxy) pregnane admixed with I unchanged 3,1 1..-diketol7,i20-dihydroxy-pregnane; separating the nonacidic 3,11-diketo-17,20-dihydroxy pregnane from and Li -3,1l-diketo-pregnane with osmium tetroxide to produce a mixture containing 3,11 diketo-17,20-dihydroxy-pregnane, 3,11-diketo- ZQ-(a) -'21-' dihydroxy pregnane, and 3,11-diketo- 20-93) -21-dihydroxy-pregnane; reacting this mixture with succinic anhydride and pyridineto convert the stereoisomers of 3,11-diketo -20,21- 'dihydroxy-pregnane to the corresponding stereo- -isomers of 3,11-diketo-20-hydroxy-21 (-carboxypropionoxy)-pregnane admixed with unchanged 3,11 diketo-17,20,dihydroxy-pregnane; separating the nonacidic 3,11-diketo-17,20-dihydroxypregnane from this mixture and reacting compound with acetic anhydride and pyridine to produce 3,11 diketo 1'7 -'hydroxy-20'-acetoxy pregnane; purifying this compound by fractional crystallization from ethyl acetate, and hydrolyzingto produce the desired 3, 1-diketo-17,2Q- dihydroxypregnane in substantially pure form. j-

3. The process of separating 3,11-diketo-1'7,20- 'dihydr'oxy-pregnane from a mixture containing this isomer admixed with stereiosomers of 3,11,- dik'eto-'20,2l-dihydroxy-pregnane which comprises reacting said mixture with acyclic anhy dride of a dicarboxylic acid to produce a mixture comprising unreacted 3,11 -diketo-17,20-dihydroxy-pregnane admixed with the stereoi'someric 3,11-diketo-20-hydroxy-21 (carboxy-acy1oxy):- pregnane; and separating the non-acidic 3,11- diketo-17,20.-dihydroxy-pregnane .from this mixture. I t

4. The process of separating 3,11-diketo-17,20-

dihydroxy-pregnane from a mixture containing this isomer admixed with stereoisomers of 3,11.--

diketo-20-21,-dihydroxy-pregnane, which comprises reacting' said mixture with succinic anhy dride and pyridine .to produce a mixture comprising unreacted 3,11 diketo-17,20*dihydroxy-pregnane admixed with stereoisomeric 3,11-diketo-20- hydroxy-21 (p-carboxy-propionoxy) -pregnane; and separating the non-acidic 3,11-diketo-17,20- dihydroxy-pregnane from this mixture by selective extraction from'aqueous alkaline solution by means of a water-immiscible organic solvent.

' 5. 3,11-diketo-17,20-dihydroxymregnane, having a melting point of about 186-187? C. and an (amapproximately equal to +47 in acetone.

6. 3,11-diketo-17-hydroxy-=20-acetoxy pregnanejhaving a melting point of about 227-229 C and an (c013 approximately equalto +75 in acetone. I r 7. 20.-substituted 3,11 diketo 17 hydroxypregnanes in which the substituent in the '20- position is a lower aliphatic carboxylic acyloxy radical. 7

' LEWIS HASTINGS SARETT.

REFERENCES CITED The following references-are of record in the file of this patent:

816,852 France May 10,1937 

1. THE PROCESS OF PREPARING 3,11-DIKETO-17,20DIHYDROXY PREGNANE IN SUBSTANTIALLY PURE FORM, WHICH COMPRISES REACTING A MIXTURE CONTAINING $**17,20-3,11-DIKETO-PREGNANE AND $**20,21-3,11-DIKETOPREGNANE WITH A COMPOUND SELECTED FROM THE CLASS WHICH CONSISTS OF OSMIUM TETROXIDE AND HYDROGEN PEROXIDE TO PRODUCE A MIXTURE CONTAINING 3,11-DIKETO-17,20-DIHYDROXY PREGNANE, 3,11DIKETO- 20 - ALPHA - 21 DITHYDROXY PREGNANE, AND 3,11-DIKETO-20-BETA-21-HYDROXY-PREGNANE; REACTING THIS MIXTURE WITH A CYCLIC ANHYDRIDE OF A DICARBOXYLIC ACID TO CONVERT THE 20,21-DIHYDROXY CARBOXYLIC ACID TO CONVERT THE 20,21-DIHYDROXY STEREOISOMERS TO THE CORRESPONDING STEROISOMERS OF 3,11-DIKETO-20-HYDROXY-21-(CARBOXY-ACYLOXY) PREGNANE ADMIXED WITH UNCHANGED 3,11-DIKETO17,20-DIHYDROXY-PREGNANE; SEPARATING THE NONACIDIC 3,11-DIKETO-17,20-DIHYDROXY PREGNANE FROM THIS MIXTURE; REACTING THIS COMPOUND WITH AN ACYLATING AGENT TO PRODUCE 3,11-DIKETO-17-HYDROXY-20-ACYLOXY-PREGNANE; PURIFYING THIS ACYLOXY DERIVATIVE BY FRACTIONAL CRYSTALLIZATION; AND HYDROLYZING TO PRODUCE THE DESIRED 3,11-DIKETO17,20-DIHYDROXY PREGNANE IN SUBSTANTIALLY PURE FORM. 